Analysis of TBX1 variation in patients with psychotic and affective disorders

Abstract

A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders, including schizophrenia and other psychotic and affective symptoms, and the responsible gene/s are assumed to also play a significant role in the etiology of nonsyndromic psychiatric disease. The most common psychiatric diagnosis among patients with 22q11DS is schizophrenia, thought to result from neurotransmitter imbalances and also from disturbed brain development. Several genes in the 22q11 region with known or suspected roles in neurotransmitter metabolism have been analyzed in patients with isolated schizophrenia; however, their contribution to the disease remains controversial. Haploinsufficiency of the TBX1 gene has been shown to be sufficient to cause the core physical malformations associated with 22q11DS in mice and humans and via abnormal brain development could contribute to 22q11DS-related and isolated psychiatric disease. 22q11DS populations also have increased rates of psychiatric conditions other than schizophrenia, including mood disorders. We therefore analyzed variations at the TBX1 locus in a cohort of 446 white patients with psychiatric disorders relevant to 22q11DS and 436 ethnically matched controls. The main diagnoses included schizophrenia (n = 226), schizoaffective disorder (n = 67), bipolar disorder (n = 82), and major depressive disorder (n = 29). We genotyped nine tag SNPs in this sample but did not observe significant differences in allele or haplotype frequencies in any of the analyzed groups (all affected, schizophrenia and schizoaffective disorder, schizophrenia alone, and bipolar disorder and major depressive disorder) compared with the control group. Based on these results we conclude that TBX1 variation does not make a strong contribution to the genetic etiology of nonsyndromic forms of psychiatric disorders commonly seen in patients with 22q11DS.

Figure 1

Linkage disequilibrium (LD) at the TBX1 locus and location of SNPs. The genomic organization of the TBX1 gene is shown above. Exons 1–9A, 9B, and 10 are symbolized by vertical bars. The star represents a known enhancer (64). Below, the underlying LD structure is shown. LD strength is symbolized by shades of red (the darker the higher). Solid black lines show three haplotype blocks. SNP identification numbers are listed on the right. SNPs selected for genotyping cases and controls are circled.

Figure 2

Linkage disequilibrium (LD) in the association sample. Pairwise LD between the nine SNPs genotyped in the association sample is shown in Table 1. Haplotypes as well as their frequencies are listed in Table 2.